Mechanisms and therapeutic strategies of BiP-HSPA9 axis-mediated endoplasmic reticulum-mitochondria crosstalk driven by bile acids in gastric intestinal metaplasia.

Gastric intestinal metaplasia (IM) is a critical precancerous lesion for gastric cancer (GC), strongly associated with bile reflux. While bile acids (BAs) are known drivers of IM, the underlying molecular mechanisms remain elusive. Here, we integrated multi-omics analysis, clinical validation, and preclinical models to elucidate the role of endoplasmic reticulum (ER)-mitochondria crosstalk in IM pathogenesis. We identified that the ER stress (ERS) sensor BiP was significantly upregulated in patients with bile reflux-associated IM. In a deoxycholic acid (DCA)-induced IM model using INS-GAS mice, pharmacological inhibition of IRE1α attenuated gastric mucosal injury and metaplastic progression. Mechanistically, we demonstrated that the mitochondrial chaperone HSPA9 acted as a critical effector at mitochondria-associated membranes (MAMs). Activation of the BiP-IRE1α-XBP1 axis upregulated HSPA9, facilitating excessive ER-to-mitochondria Ca2+ transfer. This calcium overload triggered mitochondrial dysfunction and oxidative stress, driving gastric epithelial transdifferentiation. Furthermore, network pharmacology identified quercetin as a novel BiP inhibitor. We validated that quercetin stabilized BiP conformation, suppressed the IRE1α-XBP1-HSPA9 signaling axis, and restored ER-mitochondrial Ca2+ homeostasis, thereby mitigating oxidative stress and alleviating DCA-induced IM. These findings unveil a pathogenic ER-mitochondria signaling axis and highlight HSPA9 as a potential therapeutic target, suggesting quercetin as a promising chemopreventive strategy for intercepting GC progression.